Pharmaceutically active 2-omega-aminoalkoxydiphenylmethylmethanes

ABSTRACT

2-Omega-aminoalkoxydiphenylmethylmethanes have been found useful for palliating conditions of depression in warm blooded animals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.646,521 filed Jan. 5, 1976 and now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to 2-omega-aminoalkoxydiphenyl-methylmethane andderivatives thereof which are pharmacologically active asantidepressants.

SUMMARY OF THE INVENTION

This invention relates to a compound of the formula (I): ##STR1##wherein R is selected from the group consisting of amino, C₁ -C₅alkylamino and C₂ -C₆ dialkylamino, and n is an integer of 4; or apharmaceutically acceptable acid addition salt thereof.2-(3-Dimethylaminopropxy)diphenylmethylmethane or a pharmaceuticallyacceptable acid addition salt is included within the purview of thisinvention.

This invention also relates to a method of palliating conditions ofdepression in warm blooded animals, particularly mammals, whichcomprises administering to said animal an antidepressant effectiveamount of a compound of Formula I or2-(3-dimethylaminopropoxy)diphenylmethylmethane, or a pharmaceuticallyacceptable acid addition salt-thereof.

DESCRIPTION OF THE INVENTION

As summarized above, this invention relates to a group of compoundsuseful as pharmaceutical agents, which compounds are those representedby Formula I above, and 2-(3-dimethylaminopropoxy)diphenylmethylmethane.

In Formula I, R is amino, alkylamino of 1-5 (preferably 1-3) carbonatoms, such as methylamino, ethylamino, propylamino, butylamino or thelike, or dialkylamino of 2-6 (preferably 2-4) carbon atoms, such asdimethylamino, diethylamino, dipropylamino, dibutylamino or the like;and n is an integer of 4.

Illustrative of the compounds of this invention are the following:

2-(3-dimethylaminopropoxy)diphenylmethylmethane

2-(4-aminobutoxy)diphenylmethylmethane

2-(4-methylaminobutoxy)diphenylmethylmethane

2-(4-dimethylaminobutoxy)diphenylmethylmethane

The pharmaceutically acceptable acid addition salts of the abovecompounds are, of course, also included within the scope of thisinvention.

It will be understood that the term "pharmaceutically acceptable acidaddition salts" as used herein is intended to include non-toxic salts ofthe compounds of this invention with an anion. Representative of suchsalts are hydrochlorides, hydrobromides, sulfates, phosphates, nitrates,acetates, succinates, adipates, propionates, tartrates, maleates,citrates, benzoates, toluenesulfonates, and methanesulfonates.

Of the compounds of this invention, it will be understood that thefollowing compounds are most preferred due to their high level ofantidepressant activity and their low level of toxicity.

2-(4-methylaminobutoxy)diphenylmethylmethane

2-(4-dimethylaminobutoxy)diphenylmethylmethane

2-(3-dimethylaminopropoxy)diphenylmethylmethane

PREPARATION

The compounds of this invention are prepared by reacting anomega-halogenoalkoxydiphenylmethylmethane with an amine.

The omega-halogenoalkoxydiphenylmethylmethane starting materials whichare represented by Formula II above can be prepared by reacting2-hydroxydiphenylmethylmethane with 1,3-dihalogenopropane,1,4-dihalogenobutane or 1,5-dihalogenopentane in the presence of analkali.

The amine starting materials which are represented by Formula III aboveinclude ammonia; primary amines such as methylamine, ethylamine,isopropylamine and the like; secondary amines such as dimethylamine,diethylamine, N-methylethylamine and the like.

The amine reacts with the equimolecular amount of theomega-halogenoalkoxydiphenylmethylmethane. However, the use of theexcess amine accelerates the reaction. Normally, the amount of the amineto be employed is in the range of 1 to 100 moles per 1 mole of theomega-halogenoalkoxydiphenylmethylmethane.

The reaction can be carried out without an added solvent. However, theuse of a reaction-inert solvent makes the homogenous reaction possible.

Examples of such solvents are water, dioxane, tetrahydrofuran, dimethylsulfoxide, lower aliphatic alkohols and the mixture thereof.

The reaction temperature is not critical, but normally ranges from roomtemperatures to 150° C.

The reaction time varies widely with the reaction temperature and thereactivity of the starting materials, but normally is in the range offrom 10 minutes to 40 hours.

The presence of bases which neutralize a hydrogen halide formed in thecourse of the reaction accelerates the reaction.

Examples of such bases are inorganic bases such as potassium hydroxide,sodium hydroxide, potassium carbonate, sodium carbonate and the like;and tertiary amines such as pyridine, triethylamine and the like.

The amount of the base to be employed is normally in the range of 1 to 5moles per one mole of the omega-halogenoalkoxydiphenylmethylmethane.

When the base is absent, the omega-aminoalkoxydiphenylmethylmethanesreact with a hydrogen halide formed during the reaction, and areconverted to the acid addition salts thereof.

Acid addition salts of the 2-omega-aminoalkoxydiphenylmethylmethanes maybe conveniently prepared by contacting the compounds with a suitableacid.

The 2-omega-aminoalkoxydiphenylmethylmethanes and the acid additionsalts thereof may be purified by recrystallization employing a suitablesolvent such as alkohol-ether.

Pharmacological testing of the 2-omega-aminoalkoxydiphenylmethylmethaneshas demonstrated that they are useful as antidepressant agents asevidenced by their ability to reverse reserpine hypothermia in mice.

Anitconvulsant activity has also been found in the compounds of thisinvention.

The compounds have been tested in mice for antidepressant, sedative,anticonvulsant and anticholinergic activity. The compounds wereadministered intraperitoneally and the activities of the compounds werecompared with those of Amitriptyline.

Antidepressant activity was evaluated by antagonisum of reserpine (5mg/kg i.p.) induced hypothermia (P. S. J. Spencer in "AntidepressantDrugs" S. Garattini and M. N. G. Duhes, ed., Excerpta Medica Foundation,Amsterdam, pages 194-204 (1967) and antireserpine activity was expressedas relative potency (Amitriptyline = 1). LD50 was calculated byLitchfield-Wilcoxon method.

CNS depressant activity was defined by the ability of the compounds tocause neurological deficit as measured by traction test (S. Courvoisier,R. Ducrot, L. Julou; "Psychotropic Drugs" ed. by S. Garattini, V,Ghetti, page 373, (1957) and spontaneous motor activity (Spontaneousmotor activity was measured by ANIMEX apparatus).

Anticonvulsant activity was determined by antagonism of electroshockinduced tonic extensor (L. S. Goodman, M. Singh Grewal, W. C. Brown andE. A. Swinyard, J. Pharmacol, Exptal. Therap., 108, 168 (1953)).

Central anticholinergic effect was assessed by testing the tremorineindueed tremor in mice (G. M. Everett, L. E. Bloucus and J. M. Sheppard,Science 124 79 (1956)).

Results are summarized in Table I and Table II, in which ED50 is definedas the dose of the test compounds, which prevent 50% of each responce.

                  Table I.                                                        ______________________________________                                        Antireserpine Activity in Mice                                                                   Relative LD50                                              Compound           Potency  (mg/kg i.p.)                                      ______________________________________                                        2-(4-methylaminobutoxy)diphenyl-                                              methylmethane hydrochloride                                                                      0.66     140                                               2-(4-dimethylaminobutoxy)diphenyl-                                            methylmethane hydrochloride                                                                      0.36     110                                               2-(3-dimethylaminopropoxy-                                                    diphenylmethylmethane                                                                            0.34     155                                               hydrochloride                                                                 Amitriptyline      1.00      65                                               ______________________________________                                    

                                      Table II.                                   __________________________________________________________________________                          Spontaneous                                                     Anti-  Muscle Motor                                                           convulsant                                                                           Relaxant                                                                             Activity                                                                             Antitremorine                                            Activity                                                                             Action Depression                                                                           Effect                                                   ED50   ED50   ED50   ED50                                             Compound                                                                              (mg/kg i.p.)                                                                         (mg/kg i.p.)                                                                         (mg/kg i.p.)                                                                         (mg/kg i.p.)                                     __________________________________________________________________________    2-(4-methyl-                                                                  aminobutoxy)-                                                                 diphenylmethyl-                                                                       25     >60    32     20                                               methane                                                                       hydrochloride                                                                 Amitriptyline                                                                         16     15     18      4                                               __________________________________________________________________________

It will be apparent from Tables I and II that2-(4-methylaminobutoxy)diphenylmethylmethane exhibits antireserpineactivity comparable to that of Amitriptyline, while it exhibits lowtoxicity, weak CNS depressant and anticholinergic action.

The compounds of this invention can be administered by any means thateffects palliating conditions of depression in warm-blooded animals.

For example, administration can be parenterally, subcutaneously,intravenously, intramuscularly, or intraperitoneally. Alternatively orconcurrently, administration can be by the oral route. The dosageadministered will be dependent upon the age, health and weight of therecipient, the extent of depression, kind of concurrent treatment ifany, frequency of treatment, and the nature of the effect desired.Generally, a daily dosage of active ingredient compound will be fromabout 0.5 to 50 mg per kg of body weight. Normally, from 1 to 30 mg perkg per day, in one or more applications per day is effective to obtainthe desired result.

The compound of Formula I can be employed in dosage forms such astablets, capsules, powder packets, or liquid solutions, suspensions, orelixirs, for oral administration, or sterile liquid formulations such assolutions or suspensions for parenteral use. In such compositions, theactive ingredient will ordinarily always be present in an amount of atleast 0.5% by weight based on the total weight of the composition andnot more than 90% by weight.

Besides the active ingredient of this invention, the composition willcontain a solid or liquid non-toxic pharmaceutical carrier for theactive ingredient. In one embodiment of a composition, the solid carriercan be a capsule of the ordinary gelatin type. In the capsule will befrom about 30-60% by weight of a compound of Formula 1 and 70-40% of acarrier. In another embodiment, the active ingredient can be tabletedwith or without adjuvants, or put into powder packets. These capsules,tablets and powders will generally constitute from about 5% to about 95%and preferably from 25% to 90% by weight of active ingredient. Thesedosage forms preferably contain from about 5 to about 500 mg of activeingredient, with from about 25 to about 250 mg being most preferred.

The pharmaceutical carrier can be a sterile liquid such as water andoils including those of petroleum, animal, vegetable or syntheticorigin, such as peanut oil, soybean oil, mineral oil, sesame oil, andthe like.

In general, water saline, aqueous dextrose and related sugar solutions,and glycols such as ethylene glycol, propylene glycol and polyethyleneglycol are preferred liquid carriers, particularly for injectiblesolutions such as saline will ordinarily contain from about 0.5% to 20%and preferably about 1 to 10% by weight of the active ingredient.

As mentioned above, oral administration can be in a suitable suspensionor syrup, in which the active ingredient normally will constitute fromabout 0.5 to 10% by weight. The pharmaceutical carrier in suchcomposition can be a watery vehicle such as an aromatic water, a syrupor a pharmaceutical mucilage.

The following examples are presented to further illustrate thepreparation of the compounds of this invention.

EXAMPLE 1

A solution of 5.0 g of 2-(4-bromobutoxy)diphenylmethylmethane, 20 ml of40% methylamine aqueous solution, and 100 ml of ethanol is allowed tostand at room temperature for 8 hours. Ethanol and excess methylamineare distilled in vacuo, 2N--NaOH aqueous solution is added, and thereaction product is extracted with ether. The ether solution isdistilled, 2N--HCl solution is added and the solution is evaporated todryness.

The residue is recrystallized from ethanol-ether to give 4.4 g (92%yield) of 2-(4-methylaminobutoxy)diphenylmethylmethane hydrochloride,m.p. 155°-158° C.

Analysis -- Calcd. for C₁₉ H₂₅ NO·HCl (percent) C, 71,34; H, 8.19; N,4.38 Found (percent): C, 71.05; H, 8.31; N, 4.41

EXAMPLE 2

A solution of 5.0 g of 2-(4-bromobutoxy)diphenylmethylmethane and 6 g ofdimethylamine in 100 ml of ethanol is heated at a temperature of 50° Cfor 3 hours in a sealed tube. Ethanol and excess dimethylamine aredistilled in vacuo, 2N-NaOH aqueous solution is added, and the reactionproduct is extracted with ether. Dry hydrogen chloride gas is passedinto the ether solution, and the precipitate collected by filtration.Recrystallization from ethanolether gives 4.5 g (89% yield) of2-(4-dimethylaminobutoxy)diphenylmethylmethane hydrochloride, m.p.117.5-119.0° C.

Analysis -- Calcd. for C₂₀ H₂₈ NO·HCl (percent): C, 71.94; H, 8.45; N,4.20. Found (percent): C, 71.80; H, 8.58; N, 4.05

EXAMPLES 3-7

The compounds in the following table were prepared according to theprocedure described in Example 1 or 2 using the appropriate startingmaterials.

    __________________________________________________________________________                                 Prepara-  Analysis                               Compound                     tion      Upper: Calcd.                          Example                 Addition                                                                           Process                                                                            m. p.                                                                              Lower: Found                           No.  Formula            Moiety                                                                             (Ex. No.)                                                                          (° C)                                                                       C  H  N                                __________________________________________________________________________          ##STR2##          HCl  1    109-111                                                                            70.68  70.83                                                                     7.91  7.88                                                                       4.58 4.54                        4                                                                                   ##STR3##          HCl  1    153-154                                                                            70.68 70.73                                                                      7.91 7.82                                                                        4.58 4.43                        5                                                                                   ##STR4##          HCl  2    142-144                                                                            71.34 71.25                                                                      8.19 8.08                                                                        4.38 4.25                        6                                                                                   ##STR5##          HCl  1    102-105                                                                            71.94 71.66                                                                      8.45 8.49                                                                        4.20 4.15                        7                                                                                   ##STR6##          HCl  1    121-122                                                                            72.49 72.38                                                                      8.69 8.67                                                                        4.03 4.00                        __________________________________________________________________________

Having now fully described the invention, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit or scope of thisinvention as set forth herein.

What is claimed as new and intended to be covered by Letters Patentis:
 1. A compound having the formula (I): ##STR7## wherein R is selectedfrom the group consisting of amino, C₁ -C₅ alkylamino and C₂ -C₆dialkylamino, and n is an integer of 4; or a pharmaceutically acceptableacid addition salt thereof.
 2. The compound of claim 1, wherein R is C₁-C₅ alkylamino or C₂ -C₆ dialkylamino.
 3. The compound of claim 2,wherein R is C₁ -C₃ alkylamino or C₂ -C₄ dialkylamino.
 4. The compoundof claim 3, which is 2-(4-methylaminobutoxy) diphenylmethylmethane 5.The compound of claim 3, which is2-(4-dimethylaminobutoxy)diphenylmethylmethane
 6. The compound of claim3, which is 2-(4-aminobutoxy)diphenylmethylmethane
 7. A compound whichis 2-(3-dimethylaminopropoxy)diphenylmethylmethane or a pharmaceuticallyacceptable acid addition salt thereof.
 8. A method for palliatingconditions of depression in warm-blooded animals which comprisesadministering to said animal an antidepressant effective amount of acompound of the formula (I): ##STR8## wherein R is selected from thegroup consisting of amino, C₁ -C₅ alkylamino and C₂ -C₆ dialkylamino,and n is an integer of 4; or a pharmaceutically acceptable acid additionsalt thereof.
 9. A method for palliating conditions of depression inwarm-blooded animals which comprises administering to said animal anantidepressant effective amount of2-(3-dimethylaminopropoxy)diphenylmethylmethane or a pharmaceuticallyacceptable acid addition salt thereof.
 10. A pharmaceutical compositionwhich comprises an amount of a compound of claim 1 effective forpalliating conditions of depression in warm-blooded animals and apharmaceutically acceptable carrier.
 11. A pharmaceutical compositionwhich comprises an amount of the compound of claim 7 effective forpalliating conditions of depression in warm-blooded animals and apharmaceutically acceptable carrier.